Synthetic Biology - Applications - Prostratin
From Keaslingwiki
Researchers
Dominik Behrendt, Jim Kirby*, Farnaz Nowroozi, Genevieve Park
…*contact for information.
Project Description
Human immunodeficiency virus type 1 (HIV), the causative agent of AIDS, may be treated with various drug combinations that effectively reduce the viral titer in the patient. However, the virus is not eliminated from the patient, as a small pool of latent virus remains. This latent virus is resistant to current drug treatments because of its inactive state, but it can emerge later in the patient’s life, resulting in full HIV infection or AIDS. This latent virus is considered to be the major known hurdle to HIV elimination from the body.
Two related compounds have recently shown great potential for the treatment of latent HIV. These compounds, prostratin (12-deoxyphorbol 13-acetate) and DPP (12-deoxyphorbol 13-phenylacetate), have been shown to activate latent HIV, thus rendering the virus susceptible to treatment using currently available drugs. Prostratin and DPP are structurally similar phorbol esters but share the distinction from other phorbol esters of being nontumor promoting. Both prostratin and DPP belong to the class of compounds known as diterpenes. Diterpenes are 20-carbon isoprenoid compounds formed from the universal precursor geranylgeranyl pyrophosphate (GGPP).
The natural supplies of prostratin and DPP are limited, as they both originate from uncommon plant sources (Homalanthus nutans and Euphorbia resinifera, respectively), and chemical synthesis routes have not been devised. In addition, H. nutans, the plant source of prostratin, inhabits the rainforest of Samoa, which is a unique and sensitive habitat. We plan to enable a supply of prostratin without unduly disturbing this precious ecosystem.
The goal of the proposed work is to develop a microbial system for the production of prostratin, DPP and related phorbol esters. The genes responsible for the synthesis of prostratin and DPP will be identified and cloned into a microbial host to enable a cheap and renewable source for these two compounds. As prostratin and DPP have similar structures and activities against HIV, there is considerable interest in investigating the activity of similar compounds. However, specific phorbol esters are extremely difficult to synthesize, and may not be available from natural sources. Therefore, one important feature of this work is to enable a source of novel phorbol esters.
Agreement between Samoa and UC Berkeley
Professor Paul Cox (University of Hawaii) played a central role in discovering the connection between prostratin and HIV. He also helped to negotiate a fair agreement between the Samoan people and the National Institutes of Health that gives 20% of the profits from any prostratin sales to the Samoan government, villages, and specific healers involved in the discovery of the anti-viral properties of H. nutans.
We decided that a new agreement should be put in place between UC Berkeley and Samoa that would a) allow UC Berkeley access to H. nutans genetic material, and b) ensure that Samoa will share in any benefits that arise from the microbial production of prostratin. The mutually attractive goal of this agreement is to provide an alternative to rainforest destruction for the production of prostratin and, at the same time, to compensate Samoa for the loss of any income that may have arisen from the production of prostratin from H. nutans.
Jay Keasling and Paul Cox participated in several meetings and traditional Kava ceremonies with 25 village chiefs in Samoa. A presentation on the technology involved in microbial production of prostratin was given by Prof. Keasling, and translated into Samoan. A benefits-sharing agreement was drafted, read aloud and a written document was provided (a discussion period in Samoan ensued). This agreement was later ratified by the Samoan Prime Minister, Tuila'epa Sailele Malielegaoi.
